Article

The Circadian Gene NPAS2, a Putative Tumor Suppressor, Is Involved in DNA Damage Response

Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520, USA.
Molecular Cancer Research (Impact Factor: 4.38). 10/2008; 6(9):1461-8. DOI: 10.1158/1541-7786.MCR-07-2094
Source: PubMed

ABSTRACT

Apart from regulating sleep and wakefulness, the circadian system may play an important role in other biological processes, including pathways involved in tumorigenesis. Two genetic association studies recently conducted by our lab have shown that a missense mutation in neuronal PAS domain protein 2 (NPAS2), a core circadian gene and transcriptional regulator, is significantly associated with risk of breast cancer and non-Hodgkin's lymphoma. Our current functional analyses provide the first in vitro evidence further demonstrating that cells with RNA interference-mediated depletion of NPAS2 fail to exhibit the expected cell cycle delay in response to mutagen treatment. DNA repair capacity, as measured by the comet assay, is also impaired. Moreover, a pathway-based PCR expression array of genes important for DNA damage signaling showed that knockdown of NPAS2 significantly represses the expression of several cell cycle and DNA repair genes. Thus, NPAS2 may play a role in tumorigenesis by affecting expression of cancer-related genes and could be considered a novel tumor suppressor.

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    • "Increased behavioral variability with age may be attributed to overall age-related changes in hypothalamic signaling pathways, including those converging upon NFκB (Jiang et al., 2001; Zhang et al., 2013). Potential mechanisms underlying this circadian dysregulation include altered NPAS2 function (Hoffman et al., 2008). Cytokines have well-established effects on hypothalamic function (Coogan and Wyse, 2008; Turnbull and Rivier, 1999); the altered immune status of both naïve and humanized NSG mice may thus contribute to circadian dysregulation. "
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    ABSTRACT: Humanized mice are frequently utilized in bench to bedside therapeutic tests to combat human infectious, cancerous and degenerative diseases. For the fields of hematology-oncology, regenerative medicine, and infectious diseases, the immune deficient mice have been used commonly in basic research efforts. Obstacles in true translational efforts abound, as the relationship between mouse and human cells in disease pathogenesis and therapeutic studies requires lengthy investigations. The interplay between human immunity and mouse biology proves ever more complicated when aging, irradiation, and human immune reconstitution are considered. All can affect a range of biochemical and behavioral functions. To such ends, we show age- and irradiation-dependent influences for the development of macrocytic hyper chromic anemia, myelodysplasia, blood protein reductions and body composition changes. Humanization contributes to hematologic abnormalities. Home cage behavior revealed day and dark cycle locomotion also influenced by human cell reconstitutions. Significant age-related day-to-day variability in movement, feeding and drinking behaviors were observed. We posit that this data serves to enable researchers to better design translational studies in this rapidly emerging field of mouse humanization.
    Full-text · Article · Sep 2015 · Biology Open
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    • "r suppressor ( Fu and Lee , 2003 ) , and by suppressing transcription of c - Myc that is an oncogene ( Fu et al. , 2002 ) . Now recent studies describe NPAS2 as a putative tumor suppressor playing an important role in DNA damage response , cell cycle control and apoptosis by activating different downstream genes ( Chen - Goodspeed and Lee , 2007 ; Hoffman et al . , 2008 ; Yi et al . , 2009 ) . Similarly , emerging data have revealed the role of NPAS2 as a risk biomarker in human cancers as significant associations were found between a missense polymorphism ( SNP rs2305160 : G>A , Ala394Thr ) in NPAS2 and risk of breast cancer ( Zhu et al . , 2008 ) , prostate cancer ( Chu et al . , 2007 ) and non - Hod"
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    ABSTRACT: Background: NPAS2 is a product of the circadian clock gene. It acts as a putative tumor suppressor by playing an important role in DNA damage responses, cell cycle control and apoptosis. Chronic lymphocytic leukemia (CLL) appears to be an apoptosis related disorder and alteration in the NPAS2 gene might therefore be directly involved in the etiology of CLL. Here, the Ala394Thr polymorphism (rs2305160:G>A) in the NPAS2 gene was genotyped and melatonin concentrations were measured in a total of seventy-four individuals, including thirty-seven CLL cases and an equal number of age- and sex-matched healthy controls in order to examine the effect of NPAS2 polymorphism and melatonin concentrations on CLL risk in a Pakistani population. Materials and methods: Genotyping of rs2305160:G>A polymorphism at NPAS2 locus was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Melatonin concentrations were determined by enzyme linked immunosorbent assay (ELISA). Statistical analysis was performed using Statistical Package for Social Sciences software. Results: Our results demonstrated no association of the variant Thr genotypes (Ala/ Thr and Thr/Thr) with risk of CLL. Similarly, no association of rs2305160 with CLL was observed in either females or males after stratification of study population on a gender basis. Moreover, when the subjects with CLL were further stratified into shift-workers and non-shift-workers, no association of rs2305160 with CLL was seen in either case. However, significantly low serum melatonin levels were observed in CLL patients as compared to healthy subjects (p<0.05). Also, lower melatonin levels were seen in shift-workers as compared to non-shift-workers (p<0.05). There was no significant difference (p>0.05) in the melatonin levels across NPAS2 genotypes in all subjects, subjects with CLL who were either shift workers or non-shift-workers. General Linear Model (GLM) univariate analysis revealed no significant association (p>0.05) of the rs2305160 polymorphism of the NPAS2 gene with melatonin levels in any of the groups. Conclusions: While low melatonin levels and shift-work can be considered as one of the risk factors for CLL, the NPAS2 rs2305160 polymorphism does not appear to have any association with risk of CLL in our Pakistani population.
    Full-text · Article · Sep 2014 · Asian Pacific journal of cancer prevention: APJCP
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    • "involvement of NPAS2 in tumorigenesis, by regulating PER2 that can act as tumour suppressor (Fu and Lee, 2003), and by suppressing transcription of c-Myc that is an oncogene (Fu et al., 2002). Now recent studies describe NPAS2 as a putative tumor suppressor playing an important role in DNA damage response, cell cycle control and apoptosis by activating different downstream genes (Chen-Goodspeed and Lee, 2007; Hoffman et al., 2008; Yi et al., 2009). Similarly, emerging data have revealed the role of NPAS2 as a risk biomarker in human cancers as significant associations were found between a missense polymorphism (SNP rs2305160:G>A, Ala394Thr) in NPAS2 and risk of breast cancer (Zhu et al., 2008), prostate cancer (Chu et al., 2007) and non-Hodgkin's lymphoma (Zhu et al., 2007). "
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    ABSTRACT: Abstract BACKGROUND: NPAS2 is a product of the circadian clock gene. It acts as a putative tumor suppressor by playing an important role in DNA damage responses, cell cycle control and apoptosis. Chronic lymphocytic leukemia (CLL) appears to be an apoptosis related disorder and alteration in the NPAS2 gene might therefore be directly involved in the etiology of CLL. Here, the Ala394Thr polymorphism (rs2305160:G>A) in the NPAS2 gene was genotyped and melatonin concentrations were measured in a total of seventy-four individuals, including thirty-seven CLL cases and an equal number of age- and sex-matched healthy controls in order to examine the effect of NPAS2 polymorphism and melatonin concentrations on CLL risk in a Pakistani population. MATERIALS AND METHODS: Genotyping of rs2305160:G>A polymorphism at NPAS2 locus was carried out by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Melatonin concentrations were determined by enzyme linked immunosorbent assay (ELISA). Statistical analysis was performed using Statistical Package for Social Sciences software. RESULTS: Our results demonstrated no association of the variant Thr genotypes (Ala/ Thr and Thr/Thr) with risk of CLL. Similarly, no association of rs2305160 with CLL was observed in either females or males after stratification of study population on a gender basis. Moreover, when the subjects with CLL were further stratified into shift-workers and non-shift-workers, no association of rs2305160 with CLL was seen in either case. However, significantly low serum melatonin levels were observed in CLL patients as compared to healthy subjects (p<0.05). Also, lower melatonin levels were seen in shift-workers as compared to non-shift-workers (p<0.05). There was no significant difference (p>0.05) in the melatonin levels across NPAS2 genotypes in all subjects, subjects with CLL who were either shift workers or non-shift-workers. General Linear Model (GLM) univariate analysis revealed no significant association (p>0.05) of the rs2305160 polymorphism of the NPAS2 gene with melatonin levels in any of the groups. CONCLUSIONS: While low melatonin levels and shift-work can be considered as one of the risk factors for CLL, the NPAS2 rs2305160 polymorphism does not appear to have any association with risk of CLL in our Pakistani population.
    Full-text · Article · Sep 2014 · Asian Pacific journal of cancer prevention: APJCP
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